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Effects of modulators of sarcoplasmic Ca²⁺ release on the development of skeletal muscle fatigue

¹Department of Human Anatomy and Physiology, University of Padova, 35131 Padova; and ²Consiglio Nazionale delle Ricerche Neuroscience Institute, Muscle Biology and Physiopathology Unit, 35121 Padova, Italy

Submitted 7 May 2003 ; accepted in final form 13 October 2003

The reduced release of Ca²⁺ from sarcoplasmic reticulum (SR) is considered a major determinant of muscle fatigue. In the present study, we investigated whether the presence of dantrolene, an established inhibitor of SR Ca²⁺ release, or caffeine, a drug facilitating SR Ca²⁺ release, modifies muscle fatigue development. Accordingly, the effects of Ca²⁺ release modulators were analyzed in vitro in mouse fast-twitch [extensor digitorum longus (EDL)] and slow-twitch (soleus) muscles, fatigued by repeated short tetani (40 Hz for 300 ms, 0.5 s^-1 in soleus and 60 Hz for 300 ms, 0.3 s^-1 in EDL, for 6 min). Caffeine produced a substantial increase of tetanic tension of both EDL and soleus muscles, whereas dantrolene decreased tetanic tension only in EDL muscle. In both EDL and soleus muscles, 5 µM dantrolene did not affect fatigue development, whereas 20 µM dantrolene produced a positive staircase during the first 3 min of stimulation in EDL muscle and a slowing of fatigue development in soleus muscle. The development of the positive staircase was abolished by the addition of 15 µM ML-7, a selective inhibitor of myosin light chain kinase. On the other hand, caffeine caused a larger and faster loss of tension in both EDL and soleus muscles. The results seem to indicate that the changes in fatigue profile induced by caffeine or dantrolene are mainly due to the changes in the initial tetanic tension caused by the drugs, with the resulting changes in the level of contraction-dependent factors of fatigue, rather than to changes in the SR Ca²⁺ release during fatigue development.

calcium release; muscle tension

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